While the cause of MS is unknown, an immune response to a self or foreign protein (antigen) is likely to play an important role. This project uses new laboratory techniques to discover and characterise potential antigens (protein molecules) and other molecules important to the cause of MS. The identification of these proteins may lead to targeted, more effective treatments for MS.
Unlike other studies, this will involve the application of new technologies to tissue from an unparalleled brain and spinal cord bank comprising greater than 300 MS cases, over 30 with disease duration of less than 3 months. The identification of an MS-specific antigen within microglial nodules in periplaque normal-appearing white matter (NAWM), or of new molecular targets in pre-phagocytic tissue integral to lesion formation/expansion, may help to unravel the pathogenesis of the disease and ultimately lead to the development of novel, targeted therapies.
MS is a globally prevalent disease that commonly results in substantial disability in younger patients during their working lives. MS also has a high economic burden to both the patient and society, with total direct and indirect costs of over A$35000 per patient per annum.
Currently available therapies are only partially effective, conferring an average reduction in relapse rate approximating 30% and little, if any, impact upon the chronic progressive phase of the illness. The development of more effective, targeted therapy has been hindered by the lack of a known MS-specific antigen, an incomplete understanding of the pathogenic sequences that take place in evolving and expanding MS lesions and inadequate animal models.
This project will address these issues by applying emerging technologies to an existing and unique bank of acute and chronic MS tissue. By utilising a combination of laser capture microdissection, advanced proteomics and immunofluorescence microscopy, we seek to establish molecular profiles that are specific to the earliest phases of tissue alteration in MS, namely the pre-phagocytic white matter lesions that characterise early disease, and the periplaque white matter surrounding expanding acute and chronic lesions that contain biomarkers of an MS-specific immune response previously identified by our group.
This work should significantly advance our understanding of the pathogenesis of events leading to the formation of classical active MS plaques and, potentially, to aid directly in the development of more effective, targeted therapies.
Dr Michael Barnett, and colleagues Professor Prineas and Dr Ben Crossett, of the University of Sydney have made excellent progress towards the aims of their project. Prof Prineas has received international acclaim and several major awards for his lifetime of achievements in MS research including in 2009, the MS International Federation’s highest accolade, the Charcot Award. Together with clinician researcher Dr Barnett and proteomics specialist Dr Crossett, the team makes a formidable force for progress in MS research.
While the cause of MS remains unknown, we do know that an autoimmune response plays an important role in disease development. Autoimmune responses carried out by inflammatory immune cells from the blood are generally accepted to initiate the cascade of events that lead to an MS lesion in the brain or spinal cord.
However, in 2008, Prof Prineas and his colleagues, sent significant ripples through the MS research community with their discovery of evidence for sick and dying brain cells that preceded the influx of inflammatory immune cells from the blood. Instead, this early damage is accompanied by activation of the local ‘house-keeping’ microglial cells that clean up damaged cells.
In order to pursue this unprecedented new avenue in MS research the team has set their sights on identifying the earliest triggers for this damage to myelin. To do this they have turned to high powered ‘proteomics’ technology.
Proteomics is the study of all the proteins that are activated and deactivated, in a particular biological situation and can amount to studying 1000s of proteins in one go.
An important and vital step in this project has been the development and refinement of an exciting method to extract proteins from preserved brain tissue, specifically targeting areas within MS lesions. Dr Barnett has painstakingly developed this highly complex, multi-step new technique. The technique, which will be of use to MS researchers worldwide and has been presented at 4 international meetings including PACTRIMS (Hong Kong 2009) and the Human Proteome Organisation (HUPO) world annual congress (Sydney, 2010).
Combining this technique with Dr Crossett’s proteomics expertise has lead the team to identify over 80 unique proteins in tissue from MS lesions compared to tissue from people with no neurological disease. This is the first crucial step in a huge undertaking as these proteins must now be individually characterised and studied.
Updated: 06 January, 2009